Method and system for combining anatomical connectivity patterns and navigated brain stimulation

ABSTRACT

When operating a brain stimulation device, it is critical to understand and control the network effects associated with the area being targeted for stimulation. The combined system and methods provided herein provides the operator with a real-time view of the brain network potentially affected by the stimulation. The system and method are capable of increasing the accuracy of diagnostic information. Additionally, disclosed herein are a system and method for combining navigated brain stimulation data and anatomical data with brain connectivity data for an individual.

FIELD OF INVENTION

The present invention relates to the mapping of brain functions andtreating disorders using a brain stimulation system and in particularthe determination of anatomical and functional relationships in thebrain.

BACKGROUND OF THE INVENTION

The aim of operating a brain stimulation device on a patient's brain maybe to either cause an evoked response for diagnostic purposes, or tocause a transient or permanent change in the brain function fortherapeutic purposes. The effectiveness of a brain stimulation methoddepends on how well the stimulating device and the stimulating energyreach the intended anatomical region being targeted.

One solution is to use a stereotactic arrangement to accomplish apositioning of stimulation equipment in relation to the targetedanatomical portions of the body. Typically stereotactic navigationdevices use anatomical images (structural images from MRI or CT) tocorrelate stereotactic instruments to individual anatomy. However, manytimes the brain anatomy of a subject undergoing stimulation has beenaltered or damaged by trauma or tumor. As such, an anatomical image ofthe subject's brain may not be sufficient to determine the functionalityof certain portions of the brain.

Diagnostic or therapeutic stimulation may have local or long-rangeeffects, depending on the anatomical and functional relationship of thetargeted area. As such, there exists a need for a method and system forproviding the operator of a stimulation device with an accurate view ofthe underlying anatomy, connections and functions specific to anindividual's brain.

SUMMARY OF THE INVENTION

It is an aspect of certain embodiments of the present invention toprovide an operator of a navigated brain stimulation system with a morecomplete and realistic view of the potentially affected brain network bythe stimulation.

It is a further aspect of certain embodiments to provide a system andmethod capable of increasing the accuracy of diagnostic information.

Still yet, it is an aspect of certain embodiments to combine navigatedbrain stimulation with brain connectivity data from an individual.

According to certain embodiments of the present invention there aredescribed herein methods for combining stimulation navigation withfunctional data. These methods are capable of being implemented withinvasive brain stimulation or, preferably, with non-invasivetranscranial stimulation. Such methods comprise some or all of thefollowing steps: acquiring one or more anatomical image of a brain,acquiring functional data of the brain and combining the anatomicalimage with the functional data. Examples of anatomical images are MRIimages and CT images. Examples of functional data are positron emissiontomography (PET) data, functional magnetic resonance imaging (fMRI)data, and diffusion tensor imaging (DTI) data.

Furthermore, a system according to certain embodiments of the presentinvention comprises a stereotactic device that can be used to guide astimulating device with respect to the brain anatomy. A navigationdevice can be used to guide the stimulating device to an appropriateanatomical location where the stimulating device is activated andinduces an E-Field on or in a portion of the brain.

In accordance with certain embodiments, it is possible to reduce theuncertainty associated with existing brain mapping methods, inparticular that of image-guided (navigated) transcranial magneticstimulation and white matter fiber tracking provided by appropriatetechniques. Additionally, it is possible to aid in the planning oftherapeutic intervention e.g. surgery, placement of a cortical or deepbrain stimulator device. Still yet, embodiments of the present inventionmake resections safer by integrating information from different imagingmodalities currently in use. Furthermore, embodiments of the presentinvention help render surgical decision making objective by offeringquantitative information from different diagnostic modalities.

Embodiments of the present invention describe a stimulating deviceconnected to a navigation system comprising a real-time physics-modelingsystem and a connectivity tracking system. The combined system providesthe operator with a real-time view on the brain network potentiallyaffected by the stimulation. Additionally, not only can the stimulatingdevice be modeled, but also the predicted effect of the stimulatingdevice can be modeled and displayed.

According to an aspect of certain embodiments, it is advantageous tosupply a stereotactic positioning system with display of functionaldata, such as positron emission tomography (PET) or functional magneticresonance imaging (fMRI), to highlight functionally active areasrelevant to the procedure. Further, advances in the MRI technique calleddiffusion tensor imaging (DTI) has made it possible to map local andremote anatomical connections formed by cerebral white matter. Addinganatomical connectivity information to a positioning part of a brainstimulation device to enrich the information available to the operatorleads to better understanding of diagnostic information and moreinformed targeting of, for example therapeutic stimulation.

When operating a brain stimulation device, it is critical to understandand control the network effects associated with the area being targetedfor stimulation. The combined system provides the operator with areal-time view on the brain network potentially affected by thestimulation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows stimulated E-field locations recorded in a mapping sessionas displayed on an NBS System (left). NBS software calculates themaximum E-field locations within the cortex and color-codes themaccording to their corresponding peak-to-peak MEP amplitudes, making aheat map. Locations eliciting the largest MEPs are color-coded white inthe heat map (enlarged image, right).

FIG. 2 shows a DICOM-export of a hot spot stimulation locationvisualized on an NBS screen. The MEP maximum response for the largesthand muscle, abductor pollicis brevis (APB), is defined as the “hotspot” to be used as a seed region for tractography of the pyramidaltract. The APB hotspot is in the immediate vicinity of the tumor.

FIG. 3 shows a patient's MRI dataset, NBS mapping image and DT-imagingdata combined. Following image fusion, MEP maps from the NBS motormapping session are displayed in the 3D navigational image and can beused as seed regions for applying the tractography algorithms tovisualize the white matter tracts from the primary motor cortex. Thelocation of the largest MEP response for the APB muscle used for theseed regions is color-coded green.

FIG. 4 shows a visualization of fibers originating from the APB hot spotof FIG. 2 after converting the tractography results, without anypostprocessing, into a 3D object for export to a navigation system. Thetumor is marked in red and the APB hotspot is visualized as yellowsphere.

FIG. 5 shows examples of components of a system for combining DTI andNBS (or other stimulation) data.

FIG. 6 shows additional examples of components for a system forcombining DTI and NBS data.

FIG. 7 shows an example of the concept of connections between a seedlocation and deep and distant targets within the brain.

FIG. 8 shows an example of the concept of transcallosal white matterfibers linking the two hemispheres of the brain.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

A computer assisted stereotactic positioning system associated with astimulating device can be used to determine portions of the centralnervous system targeted by the stimulation either to guide the placementof a stimulation probe or to explain the diagnostic information oreffects caused by the stimulating device.

Different technical restrictions apply to invasive and noninvasivestimulation devices. Invasive stimulation devices can be placed indirect contact with the tissue being stimulated. Invasive devices areassumed to directly activate the tissue being in direct contact with thestimulating probe.

Non-invasive stimulation devices must typically rely on crudeapproximations of stimulation effects or rely on real-time or offlinemodeling of stimulation effects. Invasive techniques may use real-timeor offline modeling and approximations of stimulation effects inparticular for planning of installation of implantable devices andadjustments to stimulation parameters after installation and/or a trialperiod.

The following are several non-limiting examples of real-time and/oroffline modeling. For example, an activating function (AF) can bedetermined to approximate the volume of activation around a deep brainstimulation (DBS) probe. An activation function describes the electricfield induced by the stimulation probe, wherein the volume and shape ofthe electric field leading to activation depends on many deviceparameters. Depending on the observed or predicted effects caused by theactivation of the stimulation device, the operator may wish to changestimulation parameters to match a desired stimulating field patternwhich better matches the underlying anatomical structures.

Another example is given from the field of transcranial magneticstimulation (TMS). A computer aided stereotactic system can be used inpositioning a coil above an appropriate anatomical area. A physicsmodeling system or program can then be used to model the effects of aTMS coil, displaying the coil activation pattern on the brain surface orat one or more depths within the brain. Typically, a TMS coil activationpattern has a stimulation focus, i.e. an area that has a higherconcentration of electric field than the surrounding areas. The size ofthe area experiencing supra-threshold stimulation varies according tothe stimulator output. This region is the activation area (AA) oractivation volume (AV).

An example of a connectivity tracking system is given. Anatomicalconnections between brain areas can be studied using a technique calleddiffusion tensor imaging (DTI). DTI is based on the imaging of waterdiffusion using magnetic resonance imaging. Using several imagessensitive to water diffusion and mathematical post-processing of theimages, it is possible to display preferred direction of water diffusionin one or more image volume element(s) (e.g. voxel(s)).

It has been shown that cerebral white matter axons passing through avoxel are aligned with a preferred direction of diffusion. Further, itis possible to construct visualizations of virtual axons bundles orfibers using one or more mathematical means. This technique is referredas (white matter) fiber-tracking in the literature.

A typical fiber tracking algorithm, e.g. tractography algorithm,utilizes firstly diffusion sensitive MR data and some parametersdefining the boundary conditions for the algorithm, e.g. starting andstopping criteria, step length, upper limit to fiber length, possiblefiber curvature limits etc. The aim is to help the algorithm to findphysiologically meaningful fibers. The list of possible parameters andtheir values is known to those skilled in art.

A fiber-tracking algorithm can generate any number of fibers from agiven data, but often only the visualization of anatomically relevantfiber bundles is desired. Typically the operator sets a starting point(A) and a stopping point (B) for the tracking or visualization system.As a result, only those fibers connecting A to B (or vice versa) andsatisfying boundary conditions are visualized. Setting a target regioncan be simple or tedious. Based on the known subcortical anatomy, it ispossible to identify some major structures, such posterior limb ofinternal capsule (PLIC) or pons, through which fibers from motor cortexare descending. However, setting cortical target regions is far moredifficult and less obvious. Further in the presence of cortical orsubcortical lesions, setting of meaningful target regions (A or B) maybe difficult.

Embodiments of the present invention describe a stimulating deviceconnected to a navigation system comprising a physics-modeling system(real-time or offline) and a connectivity tracking system. The effect ofcertain embodiments is that the volume of the activating function (AF)as described in the literature for DBS can be used as defining thetarget region (A or B). Similarly, for TMS or other non-invasivestimulation methods, the activation volume or activation area can beused for defining the target region (A or B). Examples and embodimentsare described in more detail below.

An example of the present invention relating to white mattertractography based on navigated brain stimulation results is providedherein.

The integration of anatomical and functional studies allows, forexample, for safer resection of brain tumors located in close proximityto eloquent areas. A multimodal software solution, e.g. iPlan Cranialsoftware, Brainlab AG, Feldkirchen, Germany, allows integration andcorrelation among preoperative and intraoperative anatomical andfunctional data for comprehensive planning of neurosurgical procedures.The clinical value of the planning software is dependent on the accuracyand reliability of the patient data entered.

Diffusion tensor imaging (DTI) and white matter fibre tractography areaccepted MR-imaging techniques utilizing the concept of anisotropicwater diffusion in myelinated fibres. Tractography enables 3Dreconstruction and visualization of white matter tracts and providesinformation about the relationship of these tracts to, for example, theeloquent areas and any lesion.

An important challenge for reconstructing white matter fibers is thedefinition of a functionally meaningful seed area for starting thetracking process. In patients with brain tumors, the functionalneuroanatomy of the patient may be significantly affected by the lesionwhich makes it difficult to define seed areas based solely on anatomicallandmarks.

Navigated Brain Stimulation (NBS), also known as navigated TranscrainialMagnetic Stimulation (TMS), can be used for accurate, noninvasivemapping of portions of the brain, such as the motor cortex. NBSfunctional mapping data can be directly input into surgical or treatmentplanning softeare, such as the iPlan software solution. Additionally,the NBS data can be used as an aid in selecting originating seed areasfor white matter tractography.

NBS is a noninvasive technique for electrocortical stimulation. Insteadof generating an electric field from electrodes placed on the exposedcortex, as in intraoperative direct electrocortical stimulation (DCS),with NBS the electric field (E-field) is induced intracranially bytriggering a transcranial magnetic stimulation (TMS) coil placedexternally to the head.

When determining motor functions, the simultaneous measurement of motorevoked potentials (MEP) by electromyography (EMG) can be used toidentify and verify the motor representation areas in the cortex, in thesame manner as with DCS. Excellent resolution of the motorrepresentation areas can be achieved by using a purpose-built figureeight coil and adjusting the field strength to the individual patient'smotor threshold.

Similarly, other functions can be determined and mapped via appropriatemethods. For example, when determining speech and/or cognitive functionsa task can be presented to the subject and the subject's response to thetask can be measured/determined before, during and/or after navigatedTMS stimulation. Examples of cognitive mapping via NBS can be found inPCT/FI2012/050218 filed Mar. 5, 2012 and U.S. Provisional application61/448,676 filed Mar. 3, 2011, both of which are herein incorporated byreference in their entirety.

Compared to DCS, NBS mapping has the advantage that it is noninvasiveand can therefore be used preoperatively as an aid in surgical planningand reviewing patient selection for surgery or other therapeuticoptions.

Mapping with NBS is fully compatible with the surgical navigationparadigm since the same MRI dataset can be used as an anatomical imageas the basis of both presurgical planning and intraoperative guidance.In NBS mapping the MRI dataset can be used to link the location of theTMS-generated E-field to the individual patient's cortical anatomy.Using familiar stereotactic navigation techniques, moving the TMS coilguides the E-field location through the intracranial structures. The MRIdataset can be rendered three dimensionally by the NBS System which canbe a helpful feature for orientation and location of the corticalsomatotopy with respect to the intracranial anatomical structures.

DICOM-export of motor response maps can be exported from the NBS Systemwhich permits integration of NBS mapping data with other modalitieswithin, for example, the iPlan software.

Functional mapping of the motor cortex was performed with the NBSSystem. The data file of the mapping session was retrieved from the NBSSystem via an NBS planning station for post-processing. The maximumE-field locations were selected and verified before the motor mappingimage - generated from the corresponding MEP responses—was exported inDICOM format to a portable memory device.

FIG. 1 shows an example of Stimulated E-field locations recorded in amapping session as displayed on NBS System. The NBS software calculatesthe maximum E-field locations within the cortex and color-codes themaccording to their corresponding peak-to-peak MEP amplitudes, making aheat map. Locations eliciting the largest MEPs are color-coded white inthe heat map. An expanded view of the area surround a tumor, includingthe color-coded maximum E-field locations is shown on the right of thefigure.

From the mapping session a DICOM-export of stimulation locationsvisualized on the NBS screen can be generated. In the present example,the MEP maximum response for the largest hand muscle, abductor pollicisbrevis (APB), is defined as the “hot spot” to be used in planningsoftware as the seed region for tractography of the pyramidal tract. TheAPB hotspot in the present example is in the immediate vicinity of thetumor, shown and highlighted in FIG. 2.

The patient's MRI dataset, NBS mapping image and DT-imaging data werethen uploaded to iPlan planning software. Following image fusion, MEPmaps from the NBS motor mapping session are displayed in the 3Dnavigational image, as shown in FIG. 3. The indicated locations of motoractivity can be used as seed regions for applying tractographyalgorithms to visualize the white matter tracts from the primary motorcortex. The location of the largest MEP response for the APB muscle usedfor the seed regions is color-coded green in the figures.

FIG. 4 shows the visualization of fibers originating from the APB hotspot after converting tractography results—without anypostprocessing—into a 3D object. The 3D object may then be export to,for example, a Brainlab navigation system. Additionally, the planningmay take place in real time within an NBS system. In the figure, thetumor is marked in red and the APB hotspot is visualized as yellowsphere.

Functionally meaningful seed areas are reliably determined from thenon-invasive NBS motor mapping data and permitted a more specific whitematter fiber construction process.

The study illustrated that accurate and reliable noninvasive motormapping data can greatly facilitate tractography. DICOM export of NBSmotor mapping data can be sent to a planning system to select seedareas. Additionally, planning software can be integral within the NBSsystem in order to produce real-time visualization of white matterfiber's to the operator based on selected seeds. These methods canremove a key obstacle to the wider clinical application of DT-imagingand tractography by allowing, for example, quick, accurate, meaningfuland reliable seed selection.

NBS-guided fiber tractography can be realized as a multimodal techniquefor preoperatively generating functionally-relevant white matternetworks and validating the reconstructed fibers, as described in theexample above. Additionally, NBS can add functionality to existing andnovel planning systems for planning surgical trajectories that can helppreserve critical subcortical motor pathways, as well as cortical motorareas, for example during tumor resection.

According to certain embodiments of the present invention it isdesirable to associate activating function(s), activating volume(s)and/or activating area(s) with a fiber tracking algorithm.

A method according to such embodiments can comprise some or all of thefollowing steps; initiating stereotactic tracking of one or more tools,preparing diffusion weighted MR data for fiber tracking, matchingdiffusion data to a stereotactic frame, identifying an activatingfunction (AF), activation area (AA) or activating volume (AV) in thestereotactic space, using the AF, AA or AV for determining a targetregion (A or B), and display the resulting fibers.

Preparing diffusion weighted MR data for fiber tracking can include, forexample, image matching, eddy current correction, diffusion tensorestimation or a combination thereof. For matching diffusion data to astereotactic frame the system can us coregistration of an anatomical MRIand the diffusion MRI. Image matching and coregistration can beaccomplished by identifying anatomical landmarks from multiple imagesand/or data sets and aligning similar/identical landmarks. Additionally,in order to identifying the AF, AA or AV in real time the system mayinclude physics modeling of the stimulation device.

Methods are provided herein for combining stimulation navigation withfunctional data. These methods are capable of being implemented withinvasive brain stimulation or, preferably, with non-invasivetranscranial stimulation. Such methods comprise some or all of thefollowing steps: acquiring one or more anatomical image of a brain,acquiring functional data of the brain and combining the anatomicalimage with the functional data. Examples of anatomical images are MRIimages and CT images. Examples of functional data are positron emissiontomography (PET) data, functional magnetic resonance imaging (fMRI)data, and diffusion tensor imaging (DTI) data.

In order to combine the functional data of the brain and the anatomicalimage it may be desirable to identify common landmarks between theanatomical image and the functional data. The anatomical image andfunctional data may be combined by coregistering at least a portion ofthe functional data, said portion being associated with a portion ofinterest of the brain, with the corresponding location from theanatomical image with the aid of the common landmarks. Furthermore, thecombined view of the brain can be stereotactically aligned withtranscranial magnetic stimulation (TMS) navigation software.

The order in which the anatomical image, functional data and TMS dataare combined and/or coregistered can vary. Additionally, it may bedesirable for all of the data to be combined with each other or it maybe sufficient for some data to be only combiner or coregistered with oneother type of data. For example, the anatomical image, functional dataand TMS data may be coregistered only with a stereotactic frame utilizedby TMS navigation software. Therefore, individually the functional datais not directly combined with the anatomical image, but the data isindirectly combined via the stereotactic frame.

Additionally, it is desirable to display a combined view of the brainhaving functional data for at least a portion of interest of the brainassociated with the corresponding location on the anatomical image andTMS data. The anatomical image of the brain can also be stereotacticallyaligned with a subject's head using TMS navigation software.

When operating a brain stimulation device, it is critical to understandand control the network effects associated with the area being targetedfor stimulation. The combined information can provide the operator witha real-time view on the brain network potentially affected by thestimulation. Therefore, with a more complete and realistic view of thepotentially affected brain network by the stimulation, it is possiblefor the operator to better select a location of the brain to target witha TMS pulse based on the combined view.

As discussed above, the location on, or within, the combined view can betagged with a brain function determined from navigated TMS. The locationmay be a point or area on a surface of the brain or it may be athree-dimensional volume on or within the brain. By stimulating aplurality of particular points within an area of interest, for exampleby a grid or other arrangement, and tagging those areas with a desiredresponse or function it is possible to map a portion of the brain usingnavigated TMS based on the combined view. Additionally, at least some ofthe mapping for a particular region may be done on a regular view, e.g.anatomical image, standard head model, etc. and the data can be added orincorporated with the anatomical image when creating the combined view.The area to be mapped may be determined based on the function data.

The incorporation of the functional data with the anatomical imageallows for superior seed selection, as discussed above. Therefore, itcan be desirable to select a seed region, within a navigated TMS mappedregion, from the combined view for applying a tractography algorithm.The tractography algorithm can then be used to determine white mattertracts. The white matter tracts can then be added to the combined view,as is shown by FIG. 4.

An advantage to certain embodiments of the present invention is toprovide the tractography algorithm calculation in real-time and todisplay the results to a navigated TMS operator during stimulation.However, the present methods can also be used to apply the tractographyalgorithm in an off-line mode. Such embodiments can be used for surgicalor treatment planning, for example.

As discussed above, by using a seed location and a tractographyalgorithm it is possible to determine white matter tracts extending fromthe seed location to a distal, terminal end or ends. The terminal endscan include a deep target and/or a distant target as shown in FIG. 7.

FIG. 7 shows a representation of the present concept. A TMS coil 710 isused to produce an E-field hot spot 730 at an initial location on orwithin the patient's brain 720. The location of the E-field hot spot 730can be rendered on a head model for an operator from physics modeling.The figure shows representatively how white matter fibers 740 link thelocation of the E-field hot spot, which is at or near the surface of thebrain, to a deep target 750 within the brain. Similarly, white matterfibers 770 link the location of the E-field hot spot to a distant targetat another location, often at or near the surface of the brain. DTI andfiber tracking modules are capable of generating renderings of the whitematter connections and locations of the targets for displaying to theoperator.

A distant target, as shown in FIG. 8, can even be in the oppositehemisphere from the seed. As representatively shown in the figure, a TMScoil 840 stimulates a location 850, for example, at or near the surfaceof the brain 810 on the left hemisphere 820. Physics modeling can renderthe location of the E-field hot spot 850. In the present example, thepresence of a tumor or lesion 880 may make the stimulation of areasaround the area difficult, unreliable or undesirable. Therefore, throughDTI and fiber tracking it is possible to locate Transcallosal whitematter fibers which link distant locations in one hemisphere, 820, tothe opposite hemisphere, 830. As such, it is possible to indirectlystimulate a target area 860 in hemisphere 830 by directly stimulatingthe location 850, which is unobstructed, in hemisphere 820.

One method for verifying that a seed is a desired seed is to stimulatean area of the brain corresponding to a terminal end of white mattertracts determined by the tractography algorithm. If stimulation of theterminal end(s) produces a desired response then it is possible toverify the seed, distant/deep target and white matter tracts/fibersconnecting the two. Similarly, if stimulation of the terminal end(s)does not produce the desired response then there is a chance that theseed, determined white matter tracts/fibers and/or targets are notproper. In such situations it may be desirable to stimulate the terminalend several times with varying stimulation parameters. Additionally oralternatively, some or all of the method steps for determining theterminal end can be repeated with a different seed and/or tractographyalgorithm/ tractography algorithm parameters,

There is also presented herein a method for providing stimulation to adesired location in the brain of a subject indirectly by stimulating adifferent location intracranially connected to the first. Such methodsmay include some or all of the method steps listed above with regards tocombining stimulation navigation with functional data. Additionally,such methods described above with regards to combining stimulationnavigation with functional data may include some or all of the followingsteps. Such methods comprise the steps of; identifying a first region ofinterest of the brain, said first region typically being associated witha particular function, identifying a second region of interest of thebrain intracranial connected to said first region, wherein identifyingthe second region of interest can be based at least on the combinedview, navigated TMS mapping data or portion of the methods describedabove, and indirectly stimulating the first region of interest of thebrain by applying stimulation to the second region of interest of thebrain. For the sake of the present methods, the first and second regionsshould be distant and connected via white matter tracts as describedabove.

According to such methods, the method may be for and/or include applyinga direct and/or indirect stimulation. For example, the appliedstimulation can be at least one TMS pulse, a plurality of TMS pulsesfrom a TMS coil or a deep brain stimulation, for example a DBS probe.

In particular, for a method for use in surgical or treatment planningutilizing a DBS probe, the method may further comprise the step ofdetermining an activating function which approximates the volume ofactivation around a terminal end of one or more white matter tracts.Based on this at least one deep brain stimulation probe stimulationparameter can be determined based on the activating function.

The methods described above can be for determining and displaying whitematter tracts pre or post stimulation. For example, navigated TMS can beused to map a region of the brain to determine a particular location ofthe brain which elicits a desired or the greatest response tostimulation. Once the location which is to be used as a seed has beenlocated through this mapping then the particular seed can be selectedand used in the tractography algorithm. Such a method may intend toensure that the seed used to determine the white matter tracts isactually responsible for a particular function. However, the presentmethod can also be utilized to predict responses and white matter tractsin order to give the operator of a navigated brain stimulation system abetter visual understanding of the underlying anatomy and functionalrelationships of the subject's brain.

As such, there are described herein methods for displaying predictedintracranial connections for navigated brain stimulation. Such methodsmay include some or all of the method steps listed above with regards tocombining stimulation navigation with functional data and for providingstimulation to a desired location in the brain of a subject indirectlyby stimulating a different location intracranially connected to thefirst. Additionally, such methods described above with regards tocombining stimulation navigation with functional data and for providingstimulation to a desired location in the brain of a subject indirectlyby stimulating a different location intracranially connected to thefirst may include some or all of the following steps. Such methodscomprise the steps of; tracking a navigated TMS coil in relation to asubject's head, wherein the location and orientation of the subject'shead is co-registered with at least a portion of the combined view, e.g.with the anatomical image or combined view as a whole, determining apredicted stimulation which would be applied to the subject by the coilat a particular location, assigning the location of said predictedstimulation as a seed for a tractography algorithm, determining whitematter tracts from the tractography algorithm utilizing the predictedseed, and displaying the predicted white matter tracts on and/or withinthe combined view. According to certain embodiments the predicted whitematter tracts are calculated in real time and displayed prior tostimulation of the location.

Depending on the processing power of the system implementing the presentmethod(s) and/or the complexity of the tractography algorithm, thecalculation of predicted white matter tracts may be substantiallyreal-time or may include a delay of some length. If a delay in thecalculation is predicted or expected then it can be desirable for theoperator to manually tag the location at which they would like thesystem to predict the white matter tracts. This can be done by a knowninput mechanism, for instance when the coil is in a desired position.The position and orientation of the coil can also be logged. Once thecalculations are complete and the predicted white matter tracts aredisplayed to the operator, if the operator decides that the tracts areacceptable they can re-align the TMS coil and the system may notify orautomatically stimulate the subject when the coil is in the properposition, and optionally orientation.

Similarly, the predicted white matter tracts may indicate predictedterminal ends and may allow the operator to stimulate the predictedterminal ends, in place of or in addition to the seed area, by notifyingor automatically stimulating the subject when the coil is in the properposition, and optionally orientation. By stimulating the terminal end(s)and measuring or recording the response, it may be possible to determinethe accuracy or validity/non-validity of the seed with or withoutactually stimulating the seed location.

A system according to certain embodiments of the present inventioncomprises a stereotactic device that can be used to guide a stimulatingdevice with respect to the brain anatomy. A navigation device can beused to guide the stimulating device to an appropriate anatomicallocation where the stimulating device is activated and induces anE-Field on or in a portion of the brain.

A stereotactic neuronavigation device can guide a TMS coil, or anotherstimulating device such as cortical stimulation electrodes, tDCSelectrodes or DBS leads. Additionally, there can be an image processingmodule that processes diffusion MRI data leading to maps of anatomicalconnectivity.

Examples of systems according to the present invention include acombination of the following elements; (i) a stereotactic navigationdevice (which can be optical, magnetic, etc.), (ii) a stimulating deviceaiming to create acute or long term effects in the stimulated area (TMS,transcranial electrical, epidural electrical, optical,ultrasound—based), (iii) a radiotherapy system, said radiotherapy systemoptionally including a dose calculation system, (iv) a real time physicsmodeling system (e.g. E-field calculator) for modeling the properties ofa stimulating device, (v) an image IO-system reading the image data,(vi) an image processing system for correlating anatomical data to DTIdata (e.g. coregistration, overlaying different data sets), (vii) a DTIprocessing system, said processing system optionally capable ofprocessing other diffusion MR based data, e.g. DSI, Q-Ball data, Q-spacedata, or other connectivity data obtained from e.g. resting state-fMRI,spontaneous/stimulated EEG or spontaneous/stimulated MEG or functionalNIRS, (viii) a system correlating anatomical connectivity (DTI) orfunctional connectivity information (rs-FMRI) and stereotacticinformation, for example as shown in FIG. 6, (ix) a system correlatinganatomical connectivity (DTI), or functional connectivity information,such as rs-FMRI, MEG or EEG and stereotactic information associated witha real-time physics modeling system. An example of the system componentsis shown in FIG. 5. Such systems are capable of carrying out the methodsdescribed above.

FIG. 5 shows an example of a system 500 for carrying out a methodaccording to the description above. The system 500 has a DTI modulewhich communicates, preferably two ways, with the e-field modelingcomponent of an NBS module. The two way communication 530 includes seedsfrom the e-field modeling being sent to the DTI module for calculatingfibers and tensor processing. The DTI module is capable of sendinginformation and requests to the e-field modeling module in order to, forexample, validate fibers.

Once the DTI module has calculated, and optionally verified, one or morefibers then it can transmit the findings to the head model of the NBSmodule for display, 520, wherein the head model is in communication withthe e-field modeling module, 580. The TMS system communicates with theNBS module to control stimulation, 530. Markers, for instance, on theTMS coil and patient indicate the position of the coil and head to thetracking system, 560 and 550 respectively. The tracking system, whichtracks the coil and head positions communicates the position data withthe NBS module, 570.

The systems and methods described above have a plurality of uses. One ofthe exemplary uses is in helping determine seeds for tractographyalgorithms. The particular seed selection may be based on or includingsome of the following:

Seeding from different depths, as NBS can stimulate the brain atdifferent depths. Additionally, the selection of best number of tractsto ensure that the seed is on white matter.

Seed selection based on an excitability threshold, for example, a seedis selected from an area exceeding 60 V/m, when the subject's motorthreshold at 20 mm depth is 55 V/m.

Seed selection based on normalized motor response. Seeding can beinitiated when relation of normalized EMG (mV)/(V/m) exceeds apredefined value.

Seed selection based on normalized brain response. Seeding can beinitiated when normalized EEG response (μV)/(V/m) exceeds a predefinedvalue.

Seed selection based on image data properties. For example, when whitematter signal intensity (T1 or FA) and E-Field threshold value overlap.

Seed selection based on exclusion or inclusion, e.g. any Booleanoperation, between DTI targets and NBS responses. For example,subcortical seeds can be defined and/or chosen and the fibers inconnection to responding stimulated areas are mapped.

Seed selection based on response and non response, simultaneous displayof fibers originating from a responding and non-responding area.

The present systems and methods can also be used particularly for motormapping and corticospinal tract identification. For example, they can beused for segmentation of subcortical white matter based on combinedinformation from DTI and navigated brain stimulation device. They mayalso be used for validation of NBS responses based on existing tracts,based on the proximity of tracks.

Further uses include the selection of stimulation area(s), or gridsquares, based on overlapping information from NBS response and DTI.Cross-validation of DTI and NBS, e.g. Boolean operations between fibersand NBS responses, and selection of a number of seeds/tracts based oncortical excitability are attainable via embodiments of the presentsystems and methods.

Seeding can also be based from center of gravity or an accumulatedresponse map, the result of which may enhance the reliability ofresulting fiber tracts. Still yet, targeting of DTI based on NBSresponses, e.g. seed placed at posterior limb of internal capsule(PLIC), endpoints or targets are cortical targets obtained with thestimulating device, can be achieved.

More specifically, the present methods and systems can be used in thetreatment of depression, visual cortex mapping, speech mapping andstroke therapy to name a few. When treating depression for example, thepresent methods and system can be used to identify seed placed in limbicstructures, e.g. cingulum, or areas associated with functionalneuroimaging results, e.g. anterior cingulate gyms. Additionally, seedplacement can be identified in structures associated with identificationof BA46/BA9, such as superior longitudinal fasciculus II (SLFII). Stillyet, seed placememnt can be identified within structures associated withthe regions associated with the symptoms, speech, sensory etc.

For use in visual cortex mapping the present methods and systems can beused to identify seed placement at the optical tract or optical chiasm,for example. For use in speech mapping, the present methods and systemscan be used to identify the tracts from the Broca to the Wernicke, e.g.arcuate fasciculus, prior to or during mapping.

When used in stroke therapy, for example, the present methods andsystems can be utilized for identifying Contralateral motor stimulationareas found and targeted for reducing inhibition from the intacthemisphere. Additionally, for dealing with Aphasia, Contralateral speechprocessing areas, e.g. Broca, Wernicke, cricothyroid corticalrepresentation, can be identified for targeting for reducingcross-hemispheric inhibition from the intact hemisphere.

Furthermore, a computer readable medium or mediums may have stored thereon a set or sets of computer readable instructions for causing one ormore processors to carry out the steps of any of the methods describedabove. Said computer readable medium may be transitory or non-transitoryin nature.

Although embodiments and examples of the invention have been describedin language specific to features and/or methods, one of ordinary skillin the art will recognize countless variations and modifications offeatures from embodiments, combinations of described embodiments andexamples which would not depart from the scope of the present invention.Rather, the specific features and methods are disclosed as exampleimplementations of the present invention.

1. A method for combining non-invasive transcranial stimulationnavigation with functional data, said method comprising the steps of;acquiring an anatomical image of a brain, acquiring functional data ofthe brain, coregistering at least a portion of the functional data, saidportion being associated with a portion of interest of the brain, withthe corresponding location from the anatomical image, andstereotactically aligning the combined view of the brain withtranscranial magnetic stimulation (TMS) navigation software.
 2. A methodaccording to claim 1, further comprising the step of displaying thecombined view of the brain having functional data for at least a portionof interest of the brain associated with the corresponding location onthe anatomical image
 3. A method according to claim 1, wherein theanatomical image of the brain is stereotactically aligned with asubject's head with TMS navigation software.
 4. (canceled)
 5. A methodaccording to claim 1, further comprising the step of tagging athree-dimensional volume on or within the combined view with a brainfunction determined from navigated TMS.
 6. (canceled)
 7. (canceled) 8.(canceled)
 9. (canceled)
 10. A method according to claim 1, furthercomprising the steps of further combining navigated TMS mapping datawith the combined view and selecting a seed region, within a navigatedTMS mapped region, for applying a tractography algorithm.
 11. A methodaccording to claim 10, further comprising the step of using said seedregion in the tractography algorithm to determine white matter tracts.12. A method according to claim 11, further comprising the step ofcombining the white matter tracts with the combined view and displayingthe white matter tracts on or within the combined view.
 13. (canceled)14. A method according to claim 10, wherein a tractography algorithm isapplied in real-time and the results are displayed to a navigated TMSoperator during stimulation or off-line wherein the results are used forsurgical or treatment planning.
 15. (canceled)
 16. A method according toclaim 10, further comprising stimulating an area of the braincorresponding to a terminal end of white matter tracts determined by thetractography algorithm.
 17. A method according to claim 16, furthercomprising verifying an intracranial connection between the seed regionand the terminal end region by navigated TMS mapping of the terminal endregion.
 18. A method according to claim 16, further comprisingdetermining a new seed region and repeating at least a portion of themethod steps thereafter if the terminal end region does not correspondto the function of the seed region.
 19. A method according to claim 1,further comprising the steps of; identifying a first region of interestof the brain associated with a particular function, identifying a secondregion of interest of the brain intracranial connected to said firstregion based at least on the combined view and/or navigated TMS mappingdata, and indirectly stimulating the first region of interest of thebrain by applying stimulation to the second region of interest of thebrain.
 20. (canceled)
 21. A method according to claim 19, wherein theapplied stimulation is at least one TMS pulse, a direct stimulation or adeep brain stimulation.
 22. (canceled)
 23. (canceled)
 24. A methodaccording to claim 19, further comprising the step of determining anactivating function which approximates the volume of activation around aterminal end of one or more white matter tracts.
 25. (canceled) 26.(canceled)
 27. A method according to claim 10, wherein the seedselection is based on an area which when stimulated produces anormalized EMG or EEG response exceeding a predefined value or on anarea where white matter signal intensity and an E-field threshold valueoverlap.
 28. (canceled)
 29. (canceled)
 30. A method according to claim1, further comprising the steps of; tracking a navigated TMS coil inrelation to a subject's head, wherein the location and orientation ofthe subject's head is co-registered with at least a portion of thecombined view, determining a predicted stimulation which would beapplied to the subject by the coil at a particular location, assigningthe location of said predicted stimulation as a seed for a tractographyalgorithm, determining white matter tracts from the tractographyalgorithm utilizing the predicted seed, and displaying the predictedwhite matter tracts on and/or within the combined view.
 31. A methodaccording to claim 30, wherein the predicted white matter tracts arecalculated in real time and displayed prior to stimulation of thelocation.
 32. A method according to claim 30, further comprising thestep of tagging the predicted stimulation location.
 33. (canceled) 34.(canceled)
 35. A method according to claim 1, further comprising thestep of cross-validating functional data and navigated brain stimulationdata via Boolean operations between determined white matter tracts andnavigated brain stimulation responses.
 36. (canceled)
 37. (canceled) 38.A method according to claim 1, wherein the functional data is positronemission tomography (PET) data, functional magnetic resonance imaging(fMRI) data, or diffusion tensor imaging (DTI) data.
 39. (canceled) 40.(canceled)
 41. (canceled)
 42. A system for combining Navigated BrainStimulation (NBS) and anatomical connectivity patterns, said systemcomprising; an NBS module, and a Diffuser Tensor Imaging (DTI) module incommunication with the NBS module, wherein the NBS module is configuredto provide seed's to the DTI module, and wherein the DTI module isconfigured to provide white matter tracts to the NBS module forvalidation.
 43. A system according to claim 42, wherein the NBS modulecomprises a real time physics modeling system, a stimulating device anda stereotactic navigation device.
 44. A system according to claim 42,wherein the system further comprises an image processing systemconfigured to coregister anatomical data to DTI data.
 45. A systemaccording to claim 43, wherein the physics modeling system is configuredto provide real time physics modeling of E-fields generated, or to begenerated, by the stimulating device.
 46. A system according to claim42, further comprising a display module configured to simultaneouslydisplay real time E-fields generated, or to be generated, by a portionof the NBS module and at least one calculated white matter tractcalculated by the DTI module.